(a) Technical Field
The present invention relates to imidazolylalkylcarbonyl derivatives represented by the formula 1 effective as calcium channel modulator and method of their preparation thereof.
The present invention also relates to a method for the treatment of diseases by administering the imidazolylalkylcarbonyl derivatives based on their inhibitory activity against calcium channel.

In the formula 1,
Y
is or
n is an integer of from 2 to 4, m is an integer of from 1 to 4; R1 and R2, being same or different with each other, each independently represents a hydrogen atom, C1-C8 alkyl group, substituted or unsubstituted phenyl group, or substituted or unsubstituted benzyl group; R3 is a hydrogen atom, C1-C8 alkyl group, C1-C8 hydroxyalkyl group, CH(substituted or unsubstituted phenyl)2, a heteroaromatic group having one or more hetero atom selected from O and N, substituted or unsubstituted phenyl group, or substituted or unsubstituted benzyl group; the above substituted phenyl or benzyl is respectively substituted with a substituent selected from the group consisting of halo, hydroxy, carboxy, alkoxycarbonyl, nitro, amino, mercapto, C1-C8 alkyl, and C1-C8 alkoxy groups.
(b) Background Art
The influx of calcium ions into cells through a voltage-gated calcium channels has been known to mediate numerous cellular and physiological processes including hormonal secretion, gene expression, etc. Since 1950s, the physiological importance of the influx of calcium ions through the channel proteins expressed on the cell membrane has been noticed, and calcium currents have been able to be measured under voltage-clamp conditions since 1970s (D. Gedualding, R. Gruener, J. Physiol. 1970, 211, 217-244). In 1980s, neuronal calcium channels have been classified into the two subtypes according to their voltage-dependency: high-voltage-activated (HVA) calcium channels (L-, N-, P/Q- and R-types) and low-voltage-activated (LVA) calcium channels (T-type) (R, Llinas, Y. Yarom, J. Physiol. 1981, 315, 549-567, E. Carbone, H. D. Lux, Nature, 1984, 310, 501-502, S. A. Fedulova, P. G. Kostyuk, N. S. Veselovsky, J. Physiol. 1985, 359, 431-446). While the HVA calcium channels have been named as a ‘L-type’ calcium channel due to their ‘large’ and ‘long-lasting’ currents, the LVA calcium channels have been named as a ‘T-type’ calcium channel because T-type currents are ‘tiny’ and ‘transient.’ The classification of voltage-gated calcium channels is shown below in Table 1.
TABLE 1Classification ofcalcium channelCavα1 subunitL-typeCav 1.1α1SCav 1.2α1CCav 1.3α1DCav 1.4α1FP- or Q-typeCav 2.1α1AN-typeCav 2.2α1BR-typeCav 2.3α1ET-typeCav 3.1α1GCav 3.2α1HCav 3.3α1I
As shown in Table 1, the HVA L-type calcium channels are further divided into the four subtypes, Cav1.1-Cav1.4 based on the pore-forming al subunit (α1S, α1C, α1D, and α1F). The HVA P/Q-, N-, and R-type calcium channels correspond to Cav2.1 (α1A), Cav2.2 (α1B), and Cav2.3 (α1E), respectively. The LVA T-type calcium channels are also further classified into the three subtypes, Cav3.1-Cav3.3 (α1G, α1H, and α1I). In vivo al subunits interact with other subunits such as α2-δ, β and γ to form functional voltage-gated calcium channels.
Voltage-gated calcium channels have been known to be involved in neurotransmitter secretion and synaptic transmission, and expressed mainly in the central nervous system and the peripheral nervous system. Since voltage-gated calcium channels found in the neurotransmitter system are involved in pain-signal transmission, T- and N-type calcium channels are becoming a target for the development of a novel pain killer.
The pain can be divided into acute, chronic, and neuropathic pain. Among them, neuropathic pain is caused by nerve injury and lesion or dysfunction in the nerves system resulted from trauma, viral infection, drug-induced or cancer related conditions. Neuropathic pain is associated with reorganization of spinal and cortical circuits, resulting in sensitization of sensory fibers and awakening of silent nociceptors, which causes abnormal sensory phenomena such as allododynia and hyperalgesia. Because of the complexity and diversity of the pathophyological mechanisms of neuropathic pain, successful treatments remain difficult to achieve.
N- and T-type calcium channels are present in neurons, cardiac monocytes, smooth muscle and endocrinal cells. Therefore, the increase in intracellular calcium concentration would result in damage of these cells or even lead to necrosis. Since calcium channels are an endogenous modulator of calcium concentration in cells, they have been studied as a target for various drugs such as multiple neurotransmitter drugs, hormone drugs, antihypertensive drugs, anesthetic drugs, antiarrhythmic drugs, and antiepileptic drugs (A. M. Yunker, M. W. McEnery, J. Bioenerg. Biomembranes (2003), 35, 533).
The effectiveness of N-type calcium channels as a target for the treatment of neuropathic pain has been validated by ω-conotoxin-MVIIA, a recently approved drug and its synthetic forms, Ziconotide and SNX-III, all of which are selective blockers of N-type calcium channels (Exp. Opin. Invest. Drugs 9, 2403-10; Vanegas, H. and H. Schaible (2000), Pain 85, 9-18).
N-type calcium channels also mediate the release of neurotransmitters from the sympathetic neurons, and their antagonists can be used for the treatment of cardiac diseases such as hypertension, cardiac arrhythmia, angina pectoris, myocardial infarction and congestive heart failure.
Moreover, T-type calcium channels are involved in cell development, proliferation, epilepsy, nociception, pain, and neuropathic pain, thus becoming a target for their regulation. T-type calcium channels are present in the CNS, cardiac and vascular smooth muscles, endocrine gland of adrenal gland, sinoauricular node, and heart. T-type calcium channel blockers have been known to be effective for the treatment of cerebral diseases such as epilepsy as well as cardiac diseases such as hypertension and angina pectoris [1) Hosravani, Houman et al. “Effects of Cav3.2 channel mutations linked to idiopathic generalized epilepsy”, Annals of Neurology (2005), 57, 745-749; 2) Vitko, Iuliia et al., “Functional characterization and neuronal modeling of the effects of childhood absence epilepsy variants of CACNA1H, a T-type calcium channel”, Journal of Neuroscience (2005), 25 (19), 4844-4855; 3) J.-P. Clozel, et al. Cardiovasc. Drugs Ther. (1990), 4, 731-736; 4) Hefti, F. et al. Arzneim.-Forsch. (1990), 40, 417-421; 5) Moosmang, Sven et al., “Antihypertensive Effects of the Putative T-Type Calcium Channel Antagonist Mibefradil Are Mediated by the L-Type Calcium Channel Cav1. 2”, Circulation Research (2006), 98 (1), 105-110]. Recently, it was reported that T-type calcium channel antagonists are effective for the treatment of chronic pains (Drugs of the Future (2005), 30, 573-580). For example, both mibefradil and ethosuximide, T-type calcium channel antagonists, have shown to inhibit mechanically and thermally evoked neuronal responses in spinal nerve ligation model of neuropathic pain in rats, thereby confirming that T-type calcium channel antagonists are effective for the treatment of neuropathic pain [1) Barton, Matthew E. et al., “The antihyperalgesic effects of the T-type calcium channel blockers ethosuximide, trimethadione, and mibefradil”, European Journal of Pharmacology (2005), 521 (1-3), 79-85; 2) Flatters, Sarah J. L., “T-type calcium channels: A potential target for the treatment of chronic pain”, Drugs of the Future (2005), 30 (6), 573-580; 3) Flatters, Sarah J. L. et al., “Ethosuximide reverses paclitaxel- and vincristine-induced painful peripheral neuropathy”, Pain (2004), 109 (1-2), 150-161; 4) Dogrul, Ahmet et al., “Reversal of experimental neuropathic pain by T-type calcium channel blockers”, Pain (2003), 105 (1-2), 159-168].
Gabapentin (Neurontin™) and Ziconotide (Prialt™) that act on N-type calcium channels are approved by FDA in the US as a drug for epilepsy and neuropathic pain treatments. However, they have a narrow therapeutic window due to the excess administration depending on the patient's characteristics, and show a side effect of sedating activity on the excess dosage. Mibefradil (Ro 40-5967, WO 98/49149), a T-type calcium channel blocker, had been used as a therapeutic treatment for hypertension and angina pectoris. However, mibefradil is metabolized by cytochrome P-450 3A4 and 2D6 with other drugs and interacts with them pharmacokinetically, which results in various side effects. As a result, mibefradil has been banned to sale so that there has been no T-type calcium channel blocker in a strict sense, and there is thus an urgent need for the development of a T-type calcium channel antagonist.
Since voltage-gated calcium channels are involved in neuronal diseases, they have been actively investigated as the major targets for the treatment of such diseases; for example, urea derivatives (WO 2006/024160) by Neuromed Technology Inc. and 3,4-dihydroquinazoline derivatives (Korea Patent No. 0610731), piperazinylalkyl isooxazole derivatives (Korea Patent No. 0616099), piperazinylalkylpyrazolyl-based derivatives (Korea Patent No. 0654328), and 3,4-dihydroquinazoline derivatives (Korea Patent No. 0610731) by big or mid-sized pharmaceutical companies.
The inventors of the present invention, after various efforts to develop a novel compound acting on voltage-gated calcium channels, have succeeded to synthesize novel imidazolylalkylcarbonyl derivatives and also found that they have an excellent antagonistic activity against T-type calcium channels, thereby completing the present invention.